4,5-Diamino-7H-pyrrolo{8 2,3-d{9 pyrimidine derivatives

ABSTRACT

The disclosure is directed to derivatives of 4,5-diamino-7Hpyrrolo(2,3-d)pyrimidines having the structural formula:   WHERE R1 - R4 are as defined below, and to the 4,5,6trisubstituted pyrimidines which are intermediates in their preparation. The compounds have central nervous system activity as depressants, that is, they produce a calming effect in the host.

United States Patent 191 Kim et al.

[451 Oct. 7, 1975 1 4,5-DlAMINO-7H-PYRROLO[2,3-

D]PYRlMlDlNE DERIVATIVES [75] Inventors: Dong H. Kim, Wayne; Arthur A.

Santilli, Havertown, both of Pa.

[73] Assignee: American Home Products Corporation, New York, NY.

[22] Filed: July 5, 1973 [21] Appl. No.: 376,475

Related US. Application Data [62] Division of Ser. No. 148,913, June 1,1971, abandoned, which is a division of Ser, No. 874,053, Nov. 4, 1969,Pat. No. 3,631,045,

Primary ExaminerRichard L. Raymond Attorney, Agent, or Firm-JosephMartin Weigman [57] ABSTRACT The disclosure is directed to derivativesof 4,5- diamino7H-pyrrolo[2,3-d]pyrimidines having the structuralformula:

where R R are as defined below, and t0 the 4,5,6- trisubstitutedpyrimidines which are intermediates in their preparation. The compoundshave central nervous system activity as depressants, that is, theyproduce a calming effect in the host.

4 Claims, N0 Drawings 4,5-DlAMlNO-7H-PYRROLO[ 2,3-D]PYRINHD]NEDERIVATIVES This application is a division of our application Ser. No.148.9l3 filed June l, 197], and now abandoned which was in turn adivision of our application Ser. No. 874,053 filed Nov. 4 I969 whichissued as US. Pat. No. 3,63l,045 on Dec. 28, l97l.

This invention relates to derivatives of 4,5-diamino-7-methyl-7H-pyrrolo[2,3-d]pyrimidines and to intermediates for theirpreparation. More particularly, this invention relates to new and useful4,5-diamino-7H- pyrrolol2,3-d]pyrimidine-6-carbonitriles and 4,5-diamino-7 H-pyrrolo[ 2,3-d1pyrimidine-6- carboxamides, and tointermediates in their preparation. The invention relates to thefollowing intermediates: 4,6-dihalo-5-pyrimidinecarboxaldehydes; 4,6-dihalo-5-pyrimidinecarboxaldehyde, oximes, 4,6-dihalo-5-pyrimidinecarbonitriles; 6-amino- 4-halo-5-pyrimidinecarbonitriles and 6-amino-4-methylamino-S-pyrimidinecarbonitriles.

The compounds within the purview of the present invention areexemplified by the 4.5-diamino-7H- pyrrolo[2,3-d]pyrimidines having thefollowing formula:

where R' is hydrogen or lower alkyl; R is eyano, earboxamido or loweralkoxycarbonyl; R is hydrogen or lower alkyl; and R is lower alkyl,phenyl, halophenyl,

lower alkylphcnyl, lower alkoxyphenyl or lower alkyl thio.

As used herein the terms lower alkyl" and the like describe groupscontaining from I to about 4 carbon atoms.

Typical examples of the compounds of this invention which are depictedby structural formula (I) are: 4,5-diamino-7-methyl-2-phenyl-7H-pyrrolo[2,3- dlpyrimidine-o-carbonitrileand 5-amino 4- ethylamino-2-phenyl-7H-pyrrolol 2,3-d pyrimidine6-carboxamide.

Also within the purview of the present invention are the4,5,6-trisubstituted pyrimidines exemplified by the following formulawhich, as is explained below, are intermediates in the preparation ofthe compounds having formula (I):

CHO

chlorination condensation and form lation H y it C CH=NOH N ldehydration k N R 4 Cl aminution NHR' NHR i c" I (N N rclization A Iumination J\ I R4 u g 4 N (I (Vllll) (VII) Where R -R are as describedabove.

The compounds are prepared by mixing phosphorus oxychloride anddimethylformamide in an ice bath and allowing the mixture to stand forabout A to 3 hours at a temperature of about to 25C., preferably at roomtemperature for about one hour. A 4,6- dihydroxypyrimidine is slowlyadded to the mixture and the resulting mixture allowed to stand forabout A to 1 hour. The reaction mixture then is heated for about 4 to 6hours at a temperature of about 70 to IOOC.,- preferably about hours atsteam bath temperature to afford a 4,6 -dihaIo-5-pyrimidinecarboxaldehyde (IV The first intermediate product (IV) is heated gentlywith a hydroxylamine affording the corresponding oxime:4,6-dihalo-5-pyrimidinecarboxaldehyde oxime (V). The second intermediateproduct (V) is dehydrated to a 4,6-dichloro-5-pyrimidinecarbonitrile(VI) by heating with a dehydrating agent, such as thionyl chloride, forabout 2 to 6 hours, preferably about 4 hours at reflux temperature. Thethird intermediate product is subjected to step-wise amination of thetwo halo groups. First the 4-halo group is replaced by stirring with analcohol solution of ammonia at room temperature for about A to IV:hours, preferably 1 hour, affording a6-amino-4-halo-5-pyrimidinecarbonitrile (VII).

The 6-halo group may be replaced by a substituted methylamine by mixingthe third intermediate product (VII) with substituted methylamine andheating at a temperature of about 70 to 90C. for about I to 3 hours,preferably at the reflux temperature for about 2% hours, thus affordinga 6-amino-4-substituted methylamino-S-pyrimidinecarbonitrile (VIII). Thefourth CI l C N C N c N I aminatlon I amination k c J N cl N T WS R R952 intermediate product (VIII) is cyclized by a Dieckmann typecondensation to afford the product 4,5-diamino-o-substituted-7H-pyrrolo[2,3-d]pyrimidine Where the startingmaterial contains an acetamido substituted methylamine in the6-position, the end product is a 4,5-diamino-7H-pyrrolo[2,3-dlpyrimidineo-carboxamide. Where the starting material contains acyanomethylamino group in the 6-position, the end product is a4,5-diamino-7l-l-pyrrolo[ 2,3- d]pyrimidine-6-carbonitrile.

When the reaction is completed the product (I) may be separated bystandard recovery methods. For instance, the reaction mixture may bechilled in ice and the resulting precipitate collected on a filter andthen recrystallized from absolute alkanol.

By a similar process 2-lower alkylthio derivatives of the compounds offormula I may be prepared by the following reaction scheme, where R andR are as described above, and R is lower alkyl.

NH, NH,

cyclimtion N t I 2 as l (XII The 6-amino-4-halo-2-( lower )alkyIthio-S-pyrimidine-carbonitrile starting materials may be prepared as describedin a patent application entitled 5-Amino-2,4-disubstitutedthieno[2,3-d]pyrimidine- 6-carboxylic Acid Derivatives" filed on Nov. 4,1969 as Ser. No. 874,056, and now abandoned.

The compounds may be prepared by mixing a 6- amino-4-halo-2-(lower)alkylthio-S-pyrimidinecarbonitrile with a substitutedmethylamine solution and heating at a temperature of about 60 to C. forabout 4 to 3 hours, preferably at the reflux temperature for about onehour, thus affording a 6-amino-4-methylamino 2-(lower)alkylthio-S-pyrimidinccarbonitril XXI); The latter intermediateproduct is cyclized by a Dieckma-nn type condensation to the 4,5diarniho-2-(lower) alky'lthio-7H-pyrrolo[ 2,3-d]pyrimidines XII Wherethe starting material contains an acetamido substituted methylamino inthe 6-position, the end product is a 4,5-diamino-2-(lower)alkylthio-7H-pyrrolo[2.3-dlpyrimidine-b-carboxamidc. Where the starting materialcontains a cyanomethylamino group in the 6-position, the end product isa 4,5-diamino-2- (lower)alkylthio-7Hpyrrolo[2,3-d1pyrimidine-6-carbonitrile. a if When the reaction is complete the product (XII) maybe separated by standard recovery methods.

The S-amino-4,6-disubstituted-7H-pyrrolo[ 2,3- d]pyrimidines and4,5-diamino-2-(lower)alkylthio-6-substituted-7H-pyrrolo[2,3-dlpyrimidines of the present invention haveutility in experimental and comparative pharmacology .as central nervoussystem depressants. They produce a calming effect in the host at adosage of 12.7 to 400 milligrams per kilogram of host body weight (MPK).All of the compounds are nonlethal in the dose range up to themaximumtestcd dose,

400 MPK, except 4,5-diamino-7-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidine-o-carbonitrile which is an effectivedepressant at a dose of 12.7 MPK and was found to be non-lethal in dosesas large as I27 MPK; and4,6-dichloro-Z-phenyI-S-pyrimidineearboxaldehydc, oxime which was lethalat a dose of,

12.7 MPK. The latter compound however, is a useful intermediate in theproduction of other compounds as described above, which are active ascentral nervous system depressants.

In the pharmacological evaluation of the biological activity of thecompounds of this invention, the in vivo effects are tested as follows.The compound is administered orally or intraperitoneally to three micel4 to 24 grams) at each of the following doses: 400, 127, 4(land 12.7MPK. The animals are watched for a minimum of two hours during whichtime signals of general stimulation, (i.e., increased spontaneous motoractivity, hyperactivity on tactile stimulation, twitching), generaldepression (i.e., decreased spontaneous motor activity, decreasedrespiration), autonomic activity (i.e., miosis, mydriasis, diarrhea) arenoted.

When the compounds of this invention are employed as described above,they may be administered alone or in combination with pharmacologicallyacceptable carriers, the proportionof which is determined by thesolubility and chemical nature of the compound, chosen routeofadministration and standard pharmacological practice. For example, theymay be administered orally in the form of tablets or capsules containingsuch excip ients as starch, milk, sugar, certain types of clay and soforth. They may be administered sublingually in the form of troches orlozenges in which the active ingredient is mixed with sugar and cornsyrup; and then dehydrated sufficiently to make it suitable for pressinginto a solid form. They may be administered orally in the formof-solutions which may contain coloring and flavoring agents or they maybe injected parenterally, that is intra-muscularly. intravenously orsubcutaneously. For parenteral administration they may be used in theform of a sterile solution containing-other solutes, for example, enoughsaline or glucose to make the solution isotonic.

The dosage of the present therapeutic agents will vary with the form ofadministration and the particular compound chosen. Furthermore, it willvary with the particular subject under treatment. Generally, treatmentis initiated with small dosages substantially less than theoptimum doseof the compound. Thereafter, the dosage is increased by small incrementsuntil the optimum effect under the circumstances is reached. It willgenerally be found that when the composition is administered orally,larger quantities of the active agent will be required to produce thesame effect as a smaller quantity given parenterally. In general, thecompounds of this invention are most desirably administered at aconcentration level that will generally afford effective results withoutcausing any harmful or deleterious side effects.

In order more clearly to disclose the nature of the present invention,specific examples of the practice of the invention are hereinaftergiven. It should be understood, however, that this is done solely by wayof example and is intended neither to delineate the scope of theinvention nor limit the ambit of the appended claims.

In the examples ail the temperatures are given in degrees Centigrade andthe following abbreviations are used: ml." milliliters, hr." for hours,for grams, min. for minutes, and d for the phenyl group C H5.

EXAMPLE I The following illustrates the preparation of 4,6-dichloro-2-phenyl-5-pyrimidinecarboxaldehydc which is a compound ofstructure IV.

To ml. of phosphorus oxychloride in an ice bath was added portionwise 35ml. of dimethylformamide. After allowing the resulting solution to standat room temperature for 1 hr., 25 g. of 4,6-dihydroxy-2-phenylpyrimidine was added slowly. The resulting solution was allowed tostand for 30 min. and then was heated for 5 hr. on a steam bath. Thephosphorus oxychloride was removed under reduced pressure, and theresidue was slowly poured over ice. The solid that separated wascollected on a filter and washed with water. The crude product wasrecrystallized from ethanol and then from heptane giving a producthaving a melting point of l54l56.5.

The molecular formula C I-l Cl N O was assumed for the product, andbased on that formula it was calculated that the elemental analysis byweight would be 52.50 percent carbon, 2.39 percent hydrogen, 11.07percent nitrogen and 28.02 percent chlorine. The assumed formula wasdetermined to be accurate when it was found by analysis that the productactually contained 52.28 percent carbon, 2.41 percent hydrogen, 10.99percent nitrogen and 27.77 percent chlorine. This may be expressed:

Anal. Calcd. for C,,H,,Cl N O:

C, 52.50 ',H. 2.39; N, 11.07; Cl, 28.02.

Found: C, 52.28; H, 2.4l', N, 10.99; Cl, 27.77.

The product was evaluated in the foregoing pharmacological procedure andwas found to decrease motor activity and respiration at a dose of 40 MPKadministered parenterally.

Following the procedure of Example I but substituting appropriatestarting materials, compounds having the following suhstituents may beobtained:

Example EXAMPLE ll The following illustrates the preparation of 4.6-dichloro-2-phenyl-S-pyrimidinecarboxaldehyde, oxime which is a compoundof structure V.

H=NOH To a hot solution of 3.2 g. of hydroxylaminc hydrochloride in 55ml. aqueous acetic acid (50 ml. of glacial acetic acid. ml. of water)was added l().() g. of 4,6- dichloroJ-phenyl-S-pyrimidinecarhoxaldchyde.The reaction solution was heated gently for several minutes. Water wasadded until precipitation began. Chilling in ice afforded a solid. whichwas collected on a filter and washed several times with water.Recrystallization from ethanol afforded 2.2 g. of product having amelting point of l75l77.

Anal. Calcd. for C H Cl N Oz C. 49.28; H. 2.(13:Cl. 26.45; N. 15.67.

Found: C. 49.0); H, 2.67; CI. 26.16; N, l5.62.

The product was evaluated in the foregoing pharmacological procedure andwas found to decrease motor activity and respiration at a dose of 40 MPKadministered parenterally.

Following the procedure of Example ll but substituting appropriatestarting materials. compounds having the following substituents may beobtained:

EXAMPLE lll The following illustrates the preparation of 4,6-dichloro-2-phenyl-5-pyrimidinecarbonitrile which is a compound ofstructure V.

A solution of 3.7 g. of 4,6-dichloro-2-phenyl-S-pyrimidinecarboxaldehyde, oxime and ml. of thionyl chloride was refluxedfor 4 hr. The thionyl chloride was then removed under reduced pressure.The residue (2.9 g.) was recrystallized twice from ethyl acetate withcharcoal treatment to give a pure compound having a melting point of220.5224.

Anal. Calcd. for C H Cl N z C, 52.243; H.202; Cl. 28.35; N. l6.80.

Found: C. 52.8l; H. 2.21; Cl, 28.03; N, l6.8l.

The product was evaluated in the foregoing pharmacological procedure andwas found to decrease motor activity and decrease respiration at a doseof 127 MPK administered parenterally.

Following the procedure of Example lll but substituting appropriatestarting materials. compounds having the following substituents may beobtained.

The following illustrates the preparation of 4-amino6-chloro-Z-phenyl-5-pyrimidinecarbonitrile which is a compound ofstructure VII.

CN 11 I A 01 Two and eight-tenths grams of 4.6-dichloro-2-phenyl-S-pyrimidinecarhonitrile was added to 50 ml. of ethanol saturatedwith ammonia, and the resulting mixture was stirred at room temperaturefor l hr. The precipitate which resulted was collected on a filter, andwashed with water to give 2.3 g. of product having a melting point of23724 1. Recrystallization from absolute ethanol improved the meltingpoint to 238240.

Anal. Calcd. for C H N Cl: C, 57.28; H, 3.06; N, 24.29; (1, 15.37.

Found: C, 57.06; H, 3.07; N, 24.18; Cl, 15.04v

The product was evaluated in the foregoing pharmacological procedure andfound to decrease motor activity and decrease respiration at a dose of400 MPK administered parenterally.

Following the procedure of Example 1V but substituting appropriatestarting materials, compounds having the following suhstituents may heobtained:

The following illustrates the preparation of 6-chloro-4-methylamino-2-phenyl-5-pyrimidinecarbonitrile which is a compound ofstructure Vll.

NHCH

cological procedure and found to decrease motor activity at a dose of12.7 MPK administered parenterally.

EXAMPLE V1 The following illustrates the preparation of 4-ehloro-6-ethylamino-Z-phenyl-Spyrimidineearbonitrile which is a compound ofstructure V11.

To a solution of 0.90 g. of ethylamine in 50 ml. of cold ethanol, wasadded 2.5 g. of 4.6-dichloro-2- phenyl-5-pyrimidinecarhonitrile. Afterstirring the mix' ture for 1 hr. at 0, the solid 1.8 g.) which formedwas collected on a filter. After two recrystallizations from heptane.the solid was dissolved in ether and the etherinsoluhle material wasfiltered. The ether was taken to The following illustrates thepreparation of 6-amino- 4-[ cyanomethyl )methylamino]-2-phenyl-5-pyrimidinecarbonitrile which is a compound of structure VIII.

1 CN N I )s N NCH CN A mixture of methylaminoacetonitrile hydrochloride(10.6 g.). and sodium bicarbonate 10 g.) in 70 m1. of absolute ethanolwas heated with stirring under reflux for 3 1 hr. To the refluxingmixture was added 5.6 g. of4-amino-6-chloro-2-phenyl-5-pyrimidinecarbonitrile. Refluxing wascontinued for an additional 2.5 hr. After cooling the reaction mixtureto room temperature, the inorganic salt was removed by filtration, andthe filtrate was concentrated under reduced pressure. Chilling of theconcentrated solution caused separation of crystals which were collectedon a filter and washed with water several times. Recrystallization ofthe crystals from absolute ethanol afforded 2.9 g. of product having amelting point of 202-205.

Anal. Calcd. for C H, N,,: C, 63.62; H, 4.58; N, 31.80. Found: C, 63.47;H, 4.54; N, 31.61.

The product was analysed in the foregoing pharmacological procedure andwas found to decrease motor activity at a dose of 127 MPK administeredparenterally.

Following the procedure of Example VII but substituting appropriatestarting materials, compounds having the following substituents may beobtained:

EXAMPLE VIII The following illustrates the preparation of 2-[(5-cyano-6-methylamino-2-phenyI-4- pyrimidinyl)amino1acetamide which is acompound of structure VIII.

NHCH,

To a mixture of 15.4 g. of glycinamide hydrochloride, 1 1.2 g. of sodiumbicarbonate and ml. of percent ethanol which had been refluxed for 45min. was added 7.2 g. of 4-chloro-6-methylamino-Z-phenyl-5-pyrimidineearbonitrile and the' resulting mixture was refluxed for 2 /2hr. After being chilled in ice, the mix- Cminued ture was filtered, andthe collected material was I I washed with water and then with hotbenzene. Reerys- Emmp'e R R tallizations from dimethylformamidc-watergave the I :3 2:53: 3: 2 product having a melting point of 267.5270. 5l3 -I Cali CH Anal. Caled. for C H N Oz C. 59.56; H, 5.00; N, 13 z sCIIHT CH3 29.77. Found: c, 59.85; H, 4.95; N, 29.54. ,i if, 3 33 33; fig The product was evaluated in the foregoing pharma- IX l6 3 CH,.0 H CHcological procedure and found to decrease motor activ- 5 ity at a doseof 127 MPK administered parenterally. it) x 9 4 cj i EXAMPLE lX Thefollowing illustrates the preparation of 2-(5- EXAMPLE Xcyano-6-cthylamino-2-phenyl-4- I pyrimidylamino)acetamide which is acompound of 1s The l ing lllustratcs the preparation of ,5- structureVIIL diamino-7-methyl-2-phenyl-7H-pyrrolo[2,3-

d]pyrimidine-o-carbonitrile which is a compound of structure I. NHCH..CH,. I (N n I k NHCH EONH.

CH To a mixture of l().() g. of glycinamide hydrochloride, 7.55 g. ofsodium bicarbonate and 200 ml. of 95 per- Cent ethanol which had nrefluxedvfor was To a solution containing 0.18 g. of sodium in 25 ml.added E of y "P Y of absolute ethanol was added 2.0 g. of 6-amino-4-pyrimidinecarbonitrile, and the resultant mixture wasl(cyunumethyl)methymmino] 2 pheny| 5 refluxed for 6 After being Chilledin pyrimidinecarbonitrile. The mixture was refluxed for Pound collectedon filter and washed Several l.5 hr., chilled in ice and the resultingprecipitate was Water and Wlth ether g"/mg collected on a filter to give0.5 g. of product. The prodcrystallization from dlmethylformamlde-watergave a uct was purified by recrystallizing from absolute ethw producthaving a melting point of 258-26l. n0| and decomposed at z Anal. Calcd.for c, ,H,.,N.,-o; C, 60.79; H, 5.44; N, Ana]. Calcd for CHHPZN: C 6162;H 4.58; N FOlmd= C; 61-12; H 31.80. Found: C, 63.91; H, 4.54; N, 3l.63.

P was evaluated in the forcgQing P m 40 The product was evaluated in theforegoing pharma Fologlcal P and found Fqdecrease motor acnv' cologicalprocedure and found to decrease motor activ- "Y 11 i of 400 MPKdmmlstered omuyity at a dose of I27 MPK administered parenterally.

Followmgme procdure of F P [X but subsmlut' Following the procedure ofExample X but substitutmg approljmm" staftmg materlu|s- Compounds huvmging appropriate starting materials, compounds having the followingSuhsmucms y be Obwmed? the following suhstituents may be obtained:

NHR'

(IN N (so \INCH CONH R Example R R R Example R R2 R" R i vm 0 CH H X HCN CHI, 0 IX 0 C H, H X l H CN 1 4310- lX 1 c|0 CH,, CH x 2 H (0 CH,c,.,H IX 2 p-Br0 (2H (52H; X 3 H CN C4H" p-l0-- IX 3 pl0 c,,H H x 4 C COC H, H IX 4 Fo C,H,, CH x g 5 c H CN H o-ClO- IX 5 o cm H 0 H; )4 6 CH1C0. ,C,,H H mCl0 1x o mClU- (7H,, C,.H,- x 7 C,H,, CN H p B 1x 7 pBrU (7H, C4H X s CH, co.,c ,H,, 1x s 4-CH ,0- C H, (3 H, x 9 H IX 9 2 r I u HX r 11) C3H1 CO1CH| CHHT 3-C;,HTO

The following illustrates the preparation of S-amino-4-methylamino-2-phcnyl-7H'pyrrolo{2,3- d]pyrimidine-6-carboxamide whichis a compound of structure I.

NHCH3 2 N/ l l til N N CONH2 To a sodium ethoxide solution (0.24 g.sodium, 50 ml. ethanol) was added 3.0 g. of 2-[(5-cyano-6-methyl-amino-2-phenyl-4- pyrimidinyl)amino[aeetamidc. and the mixturewas refluxed for l hr. After being chilled in ice. the solid (2.8 g.)was collected. lt was triturated with hot ethyl ace tate and filtered.The compound did not melt below 320.

Anal. Calcd. for C H N,;O: C, 59.56; H, 5.00; N, 29.77. Found: C. 59.63;H, 4.80; N, 29.51.

The product was evaluated in the foregoing pharmacological procedure andfound to decrease motor activity at a dose of 12.7 MPK administeredparenterally.

. EXAMPLE Xll The following illustrates the preparation of S-amino-4-ethylamino-Z-phenyl-7H-pyrrolo[2,3-dlpyrimidine- 6-carboxamide whichis a compound of structure I.

To a sodium ethoxide solution (0.26 g. sodium, 50 ml. ethanol) was added3.3 g. of 2-(5-cyan0-6- ethylamino-2-phenyl-4-pyrimidylamino)acetamide,and the resulting mixture was refluxed for 40 min. After being chilledin ice a solid separated and was collected on a filter, washed withwater and then ether. The product (2.5 g.) was recrystallized fromdimethylformamide and had a melting point higher than 360.

Anal. Calcd. for C H N O: C, 60.79; H, 5.44; N, 28.36. Found: C, 60.79;H, 5.45; N, 28.09.

The product was evaluated in the foregoing pharmacological procedure andfound to decrease motor activity at a dose of 400 MPK administeredparenterally.

Following the procedure of Example Xll but substituting appropriatestarting materials, compounds having the following substitutents may beobtained:

EXAMPLE XIII The following illustrates the preparation of 6-amino- 4-[cyanomethyl )methylaminol-2-methylthio-S- pyrimidinecarbonitrile whichis a compound of struc ture Xl.

CN N i K Ca s N ucH cn A mixture of methylaminoacetonitrilehydrochloride 10.6 g.) and sodium bicarbonate l0 g.) in 70 ml. ofabsolute ethanol was heated with stirring under reflux for 45 min. Tothe refluxing mixture was added 5.7 g. of6-amino-4-chloro2-methylthio-5- pyrimidinecarbonitrile. Refluxing wascontinued for an additional 2.5 hr. After cooling the reaction mixtureto room temperature. the inorganic salt was removed by filtration, andthe filtrate was concentrated under reduced pressure. Chilling of theconcentrated solution caused separation of crystals which were collectedon a filter and washed with water several times. Recrystal lization ofthe crystals from absolute ethanol afforded 3.] g. of product having amelting point of 205207.

EXAMPLE XIV The following illustrates the preparation of 2-[(6-amino--cyano-2-methylthio-4- pyrimidyl)aminolacetamide which is acompound of structure XI.

k l \N \NHCHZCONHZ To a mixture of l l g. of glycinamide hydrochloride.8.4 g. of sodium bicarbonate, and 70 ml. of 95 percent ethanol which hadbeen refluxed for 45 min. was added 5.9 g. of4-amino-6-chloro-2-mcthylthio'5- pyrimidinccarbonitrile and theresulting mixture was refluxed for 2 /2 hr. After being chilled in ice,the mixture was filtered. and the collected material was washed withwater and then with hot benzene. The crude product was recrystallizedfrom dimethylformamide giving a product which decomposed at 279-28 l".

Anal. Calcd. for C H N OS: C. 40.33; H; 4.23; N, 35.28; S, l3.43. Found:C. 40.30; H. 4.09; N, 34.82; S, 13.!0.

The product was evaluated in the foregoing pharmacological procedure andfound to decrease motor activity and respiration at a dose of 400 MPKadministered orally.

Following the procedure of Example XIV but substituting appropriatestarting materials, compounds having the following substituents may beobtained:

EXAMPLE XV The following illustrates the preparation of 4.5-diamino-7-methyl-2-methylthio-7H-pyrrolo[2,3dlpyrimidine-fi-carbonitrile which is a compound of structure XII.

CH S N N l CH3 To a solution containing 0.2 g. of sodium in 30 ml. ofabsolute ethanol was added 2.3 g. of 6-amino-4-[(cyanomethyl)-methylamino]-2-methylthio-5 pyrimidinecarbonitrile. Theresulting mixture was refluxed for l .5 hr. After cooling the reactionmixture the resulting precipitate was collected on a filter. The productamounted to L8 g. and decomposed at 238-240. Recrystallization fromabsolute ethanol raised the decomposition point of 240-242.

Anal. Calcd. for C H N S: C, 46. [5; H, 4.30; N, 35.88. Found: C, 46.02;H, 4.09; N, 35.73.

The product was evaluated in the foregoing pharmacological procedure andfound to decrease motor activity and respiration at a dose of 12.7 MPKadministered orally.

Following the procedure of Example XV but substituting appropriatestarting materials, compounds having the following substituents may beobtained:

EXAMPLE XVI The following illustrates the preparation of 4,5-diamino-Z-methylthio-7H-pyrrolo(2,3-d]pyrimidine-6- carboxamidc which isa compound of structure Xll.

' NHL.

N I l/ k CH=S/ N a cowu To a sodium ethoxide solution (0.9 g. sodium, 70ml. ethanol) was added approximately 9.5 g of 2-[(6-amino-5-cyano-2-methylthio-4- pyrimidinyl)amino]acetamide and theresulting mixture was refluxed for l hr. Aftcr being chilled in ice, thereaction product was collected on a filter and washed with a smallamount of ethanol and then with water. Recrystallization fromdimethylformamide gave L4 g. of product having a melting point higherthan 360.

Anal. Calcd. for C H N OS; C, 40.33; H, 4.23; N, 35.28; S, l3.43. Found:C, 40.05; H. 4. I6; N. 34.94; S, 13.57.

The product was evaluated in the foregoing pharmacological procedure andfound to decrease motor activity and respiration at a dose of I27 MPKadministered parentcrally.

Following the procedure of Example XVI but substituting appropriatestarting materials, compounds having the following substituents may beobtained:

What is claimed is: I. A compound selected from those having the formulaCN N/

1. A COMPOUND SELECTED FROM THOSE HAVING THE FORMULA
 2. A compound asdefined in claim 1 which is4-amino-6-chloro-2-phenyl-5-pyrimidinecarbonitrile.
 3. A compound asdefined in claim 1 which is6-chloro-4-methylamino-2-phenyl-5-pyrimidinecarbonitrile.
 4. A compoundas defined in claim 1 which is4-chloro-6-ethylamino-2-phenyl-5-pyrimidinecarbonitrile.